Environment and Heart Disease: Introduction
Toxic chemicals in the environment are known to produce a wide array of adverse effects in the heart and cardiovascular system. These harmful effects include hypertension, peripheral vascular injury, alterations of lipid levels, disturbances of cardiac rhythm, cardiomyopathy, acute myocardial infarction (MI), stroke, and sudden death. Toxic chemicals are also linked to cardiovascular disease risk factors, including obesity, insulin resistance, the metabolic syndrome, and diabetes. This chapter describes these effects.1
Beyond the known cardiotoxins, there likely are other chemicals in the modern environment whose toxicity to the heart and cardiovascular system has yet to be recognized. These cardiotoxins will be discovered among the tens of thousands of new synthetic chemicals invented and produced in the past half century. The majority of these materials have not been tested for toxicity, which is a serious failure of stewardship by the chemical industry and the US federal government.2,3 These synthetic chemicals are widely disseminated in the human environment, and national surveys conducted by the Centers for Disease Control and Prevention (CDC) find measurable levels of several hundred synthetic chemicals in the blood and urine of virtually all Americans.4
Given the continuing potential today for exposure to new chemicals of unexamined toxicity, every physician is advised to obtain a brief history of occupational and environmental exposure from every patient and to ask more detailed follow-up questions or seek consultation with a specialist in occupational and environmental medicine if the initial screen raises suspicion of toxic exposure. Straightforward screening algorithms have been developed.5 The most intense exposures typically occur in occupational settings, and most discoveries of new associations between toxic chemicals and disease have been made by physicians examining working populations.6 The possibility of etiologic discovery is high.
Cardiovascular disease caused by toxic agents in the environment is preventable. Prevention requires diagnostic recognition of the links between exposure and disease followed by evidence-based interruption of exposure.7
Metals
Lead is a heavy metal, a chemical element that comprises 0.002% of the Earth’s crust. It has a low melting point, is easily molded and shaped, and can be combined with other metals to form alloys. Because of these properties, lead has been used by humans for millennia and is used today in products as diverse as pipes, storage batteries, pigments, glazes, vinyl products, weights, shot and ammunition, cable covers, and radiation shielding. From the 1930s to the 1970s, lead was used extensively as a gasoline additive to improve engine performance.8 Lead is widespread in the modern environment. Global consumption of lead continues to increase mainly because of rising demand for large and small batteries.9
Patients may be exposed to lead by either inhalation or ingestion. Inhalation is the most common route of adult exposure and the most serious exposures occur among workers exposed occupationally.10 Workers at greatest risk include smelter and foundry workers, hazardous waste workers, construction workers exposed to lead-painted steel, shipyard workers, electrical workers, and home renovators sanding or removing old lead paint.10 For children, ingestion of lead paint chips or, more commonly, ingestion of the lead dust eroded from lead paint, is the most common route of exposure.11 Persons of all ages may be exposed by ingestion to lead in drinking water.11 Ayurvedic and other nonprescription medications are further sources of exposure.12
Lead is best known as a neurotoxin. At high levels, lead can cause acute encephalopathy with coma, convulsions, and death.11 At lower levels, it can cause injury to the central and peripheral nervous systems with loss of intelligence, shortening of attention span, disruption of behavior, and slowing of nerve conduction velocity. Children are especially vulnerable to these effects.13 There appears to be no threshold below which lead causes no injury to the human brain.13,14
Cardiovascular toxicity, specifically increased incidence of hypertension and stroke, was reported more than a century ago among workers exposed occupationally to lead.15 Recent large-scale epidemiologic studies have confirmed a relationship between lead and hypertension in the general US population even at very low blood lead levels.16-18 A recent systematic review found that the relationship between lead and hypertension is consistent across numerous high-quality studies and concluded that the association is causal.19 The hypertensive effects of lead have been confirmed experimentally19
Additionally, positive associations have been identified among lead, coronary heart disease, stroke, alterations in cardiac rhythm, and peripheral arterial disease.20-23 The number of studies examining each of these outcomes is, however, relatively small, and the associations less well established than that between lead and hypertension.19 Associations between lead and cardiovascular effects have been observed at blood lead levels as low as 5 μg/dL.19
Cadmium is a metallic element used in batteries, electronic equipment, metal coatings, and pigments. Virtually all high-dose exposure occurs in the workplace, and inhalation is the principal route of exposure.10 Workers at greatest risk include miners, smelter workers, electroplaters, battery manufacturers, and electronics workers. Nonoccupational exposure can occur through consumption of contaminated drinking water.24Tobacco contains cadmium, and smokers consistently have higher cadmium levels than nonsmokers. After it has been absorbed, cadmium is stored in the kidneys and liver and may remain in those organs for decades.25 Cadmium has been characterized as a human carcinogen by the International Agency for Research on Cancer. High level exposure to cadmium is associated with impaired renal function and lung cancer.26-28
A positive association between cadmium levels in the general US population, and increased blood pressure has been found,29 a finding that is confirmed experimentally.30 Increased cadmium burden is associated with an elevated risk of stroke, cardiac arrest, and peripheral arterial disease.31,32 Cadmium exposure in the US population is associated with elevated circulating levels of inflammatory markers such as C-reactive protein and fibrinogen.33 Cadmium has been found to be an independent risk factor for atherosclerosis, and elevated cadmium levels are associated with increased carotid arterial intima–media thickness.34,35
Mercury has been used since antiquity in pharmaceuticals and cosmetics and more recently in pesticides, dental fillings, and scientific and medical instruments. Two-thirds of all mercury in the environment is of anthropogenic origin. Combustion of coal in the generation of electricity (all coal contains some mercury) is the single major source of mercury emission in the environment. Waste incineration, including incineration of medical waste, is another important source. Mercury exists in several distinct chemical forms with quite different toxicities.36 Metallic mercury and methylmercury are the two forms most highly toxic to the cardiovascular system.
Exposure to metallic mercury occurs most commonly in industry.10 Mercury vaporizes at ambient temperature, and inhalation is the principal route of exposure. Ingestion exposure is not important because metallic mercury is poorly absorbed from the gut. Exposure to metallic mercury is seen today among gold miners, chloralkali workers, instrument makers, and workers in the electronics industry Exposure occurs also among persons who use mercury in traditional religious practices, particularly from the Caribbean region.
Acute exposure to metallic mercury is associated with pneumonitis and, at very high levels, encephalopathy. Chronic exposure is linked to peripheral neuropathy with tremor, personality changes (erethism), and renal toxicity with proteinuria.
The cardiovascular effects of chronic occupational exposure to metallic mercury include dose-related increases in hypertension, coronary heart disease, MI, increased carotid arterial intima–media thickness, cerebrovascular accident, MI, and cardiac death.37,38
Methyl mercury is formed when airborne particles of metallic mercury emitted by industrial sources deposit in lakes, rivers, and oceans. The deposited mercury is transformed to methylmercury by marine microorganisms. Methylmercury is lipophilic and highly persistent in the environment. It bioaccumulates to reach particularly high levels in predatory fish at the top of the aquatic food chain such as bluefin tuna, shark, king mackerel, and swordfish. Consumption of contaminated fish is the major route of human exposure to methylmercury.36
Methylmercury is a potent neurotoxin. The fetal brain is especially sensitive, and methylmercury crosses freely during pregnancy between the maternal and fetal circulations. Methylmercury has been associated with major outbreaks of developmental neurotoxicity, notably Minamata disease,39 as well as with widespread subclinical neurotoxicity.36
Methylmercury is also a cardiovascular toxin. Methylmercury exposure is associated with disturbances in cardiac rhythm, specifically decreased heart rate variability,40 hypertension,41,42 increased carotid arterial intima–media thickness,41 accelerated progression of carotid atherosclerosis,43 increased risk of MI,44 and increased risk of coronary and cardiovascular death.44 Epidemiologic studies of populations exposed to methyl mercury through consumption of fish and marine mammals have had to disentangle the adverse effects of methylmercury from the potentially beneficial effects of omega-3 fatty acids.45 Experimental studies corroborate the cardiovascular toxicity of methylmercury and suggest that methyl mercury may contribute to progression of cardiovascular disease by causing oxidative stress.46
Arsenic is a metalloid element. It is found worldwide in drinking water and is a particularly severe problem in southeast Asia, Taiwan, areas of northern Chile and Argentina, northern New England, and the American Southwest.47
Arsenic exposure is strongly associated with increased risk of cardiovascular disease.48,49 Positive dose-response relationships have been documented between chronic arsenic exposure and carotid atherosclerosis,50,51 hypertension,52 and ischemic heart disease.53 Arsenic exposure has also been linked to diabetes.54,55
Chronic arsenic exposure is strongly associated with peripheral vascular disease. The severity appears related to cumulative dose and is greatest when exposure begins in utero or early childhood. The most severe cases progress to endarteritis obliterans with frank gangrene of the extremities (black foot disease).56
Experimental studies support the relationship between arsenic exposure and cardiovascular disease and have found that arsenic appears to induce atherosclerosis and heart disease through enhancing oxidative stress.57
Cobalt is a relatively rare element with properties similar to iron and nickel.10 It is an essential trace element necessary for the formation of vitamin B12.
Excessive exposure to cobalt has been linked to cardiac disease. In 1966, a syndrome labeled “beer drinker’s cardiomyopathy” appeared among heavy beer drinkers in Quebec City, Canada, and was characterized by pericardial effusion, elevated hemoglobin concentrations, and congestive heart failure. The appearance of the syndrome coincided temporally with addition of cobalt to beer.58 A similar cardiomyopathy has been reported in other groups chronically exposed to cobalt, among them beer-drinking populations and workers producing “hard metal,” an alloy that contains cobalt.10,59
Experimental studies in a rat model suggest that cobalt may cause myocardial dysfunction and disease by suppressing respiratory chain enzymes in myocardial cells, thus leading to mitochondrial dysfunction.60
Thallium is a highly toxic metallic element. It has been used as a rodenticide, although this use has not been permitted in the United States since 1972. It can be absorbed orally and transdermally. It has neither an odor nor a taste and has been used in poisonings and assassinations. Symptoms of acute intoxication include gastrointestinal symptoms, polyneuropathy, and dermatologic changes. Alopecia typically develops 3 to 4 weeks after exposure.61
Cardiovascular manifestations of acute thallium poisoning are hypotension and bradycardia, apparently secondary to direct toxic effects of thallium on the sinus node and myocardium. Diagnosis is made by toxicologic screen. Because thallium exerts its toxicity by displacing potassium, treatment consists of potassium chloride and Prussian blue (potassium ferric hexacyanoferrate) plus supportive measures.61
Halogenated Hydrocarbons
The halogenated hydrocarbons are a large and diverse family of synthetic chemicals that have as their common feature a chemical bond between a carbon atom and one or more halogen atoms (chlorine, bromine, or fluorine). The carbon–halogen bond is strong, and consequently many halogenated hydrocarbons are extremely persistent in the human body and in the environment.
Halogenated hydrocarbons have been used in a wide range of products from electrical insulation (polychlorinated biphenyls [PCBs]) to flame retardants (polybrominated diphenyl ethers [PBDEs]) and water repellents (perfluorinated compounds). Some such as dioxins and furans are produced as inadvertent byproducts in chemical manufacture or released to the environment through combustion of materials containing chlorine. Because of their lipophilic nature, halogenated hydrocarbons readily cross the placenta and the blood–brain barrier. They concentrate and may persist for years in adipose tissues. Depending on their chemical composition and structure, halogenated hydrocarbons have multiple and varied toxicities, among them neurotoxicity, carcinogenicity, and ability to disrupt endocrine function. A number of halogenated hydrocarbons are toxic to the heart and cardiovascular system.
Some volatile halogenated alkanes (eg, halothane, methoxyflurane, enflurane) were used in the past as anesthetics. These compounds are cardiotoxic and depress the heart rate, conduction, and contractility. They can also provoke arrhythmias.62 Experimental evidence suggests that these compounds exert their toxicity by interacting with cardiac potassium channels as well as with calcium and sodium channels.63 This toxicity appears to be potentiated by catecholamines. These compounds have for the most part been replaced by less toxic anesthetic agents.
High-level, brief exposures to halogenated solvents (eg, trichloroethylene 1,1,1-trichloroethane) have been recognized for many decades to be associated with central nervous system intoxication and acute death, caused apparently by sudden cardiac arrhythmias.10 These exposures may occur in occupational settings and also among persons who “sniff” solvents as a means of intoxication. The suspected mechanism of toxicity, as in the case of halogenated anesthetics, appears to involve disruption of potassium, calcium, and sodium channels.63
The halogenated solvent dichloromethane (methylene chloride) is uniquely toxic to the heart and cardiovascular system because its metabolism produces significant amounts of carbon monoxide (CO). Epidemiologic studies of chemical workers occupationally exposed to dichloromethane have observed excess mortality from heart disease.64,65
Dioxins are a family of chlorinated hydrocarbon compounds with a common cyclic chemical structure. Dioxins are highly persistent in humans and the environment. They are lipophilic and bioaccumulative. Exposures to dioxin, and specifically to the highly toxic dioxin congener 2,3,7,8-tetracloro-p-dibenzodioxin (TCDD) have occurred among workers in the chemical industry, particularly workers producing herbicides66 and in military personnel in the Vietnam War who applied dioxin-contaminated herbicide (Agent Orange). In the general population, exposure results most commonly from consumption of foods, especially meats, in which TCDD has accumulated. TCDD exposure has also occurred in community populations exposed to TCDD from industrial releases.67
TCDD has been linked to cardiovascular risk factors, specifically to insulin resistance and type 2 diabetes, in studies of American and Korean Vietnam War veterans exposed militarily to TCDD-contaminated herbicide,68-70 in persons in the general US population examined through the National Health and Nutrition Examination Survey (NHANES) study,71 and in the general population of Japan.72 TCDD was associated with increased mortality from diabetes among community residents in Seveso, Italy, exposed after an industrial explosion.73 TCDD is associated with hypertension in the general US population74 and with components of the metabolic syndrome in the population of Japan.75
A recent systematic review of 12 epidemiologic studies (10 of them in occupationally exposed populations) found a consistently positive, dose-related, statistically significant association between high-level TCDD exposure and mortality from ischemic heart disease as well as a more modest association with mortality from all forms of cardiovascular disease.76
Toxicologic studies of TCDD corroborate these epidemiologic findings. Chronic exposure of rats to TCDD produced a dose-related increased incidence of degenerative cardiovascular lesions, including cardiomyopathy and degenerative arteritis.77 Mice exposed subchronically to TCDD had increased blood pressure, elevated triglycerides, elevated LDL, elevated total cholesterol, increased cardiac weight, and increased risk of cardiovascular disease.78 They also showed elevated levels of markers of oxidative stress. Atherogenic ApoE-/- mice exposed subchronically to TCDD developed earlier and more severe atherogenic plaques.79 Mixtures of TCDD and other halogenated pollutants have been shown to induce insulin resistance and to downregulate two insulin-induced genes centrally involved in lipid homeostasis.80 TCDD and structurally similar PCBs appear to exert their cardiovascular toxicity through a variety of pathophysiologic mechanisms, including oxidative stress, inflammation, and direct cardiotoxicity, possibly mediated through disruption of mitochondrial function.81
PCBs, another family of chlorinated hydrocarbons, were used in a wide variety of industrial applications, most notably as insulating liquids in electrical generators and capacitors. Because of their environmental persistence and toxicity, manufacture and use of PCBs was banned in the United States in 1977, but PCBs are still abundant in the environment, especially in marine sediments. PCBs bioaccumulate in the aquatic food chain and reach the highest levels in predatory marine species such as bluefin tuna, shark, king mackerel, and swordfish. Consumption of contaminated fish is the major current route of exposure.
The most highly cardiotoxic PCBs are congeners that most closely resemble TCDD, (eg, PCB-126). Dioxin-like PCBs have been linked to cardiovascular risk factors, specifically to components of the metabolic syndrome, high blood pressure, elevated triglycerides, and glucose intolerance74,75,82,83 and to diabetes.71,
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